Cancer is a heterogeneous disease for which curative treatment options remain elusive. The most promising treatment approaches today are molecularly targeted therapies tailored to address varied cellular defects in a tumor type- and stage-specific manner. Consequently, there is widespread interest in diagnostic and prognostic tools that aid in the identification and monitoring of molecular signaling events in tumor cells. Novel targeted therapeutics are needed that interfere with specific aberrant enzyme activities or protein interactions. The PI3K-Akt pathway is of particular interest because it is frequently hyperactivated during cancer invasion. Moreover, the progressive enhancement of PI3K-Akt signaling coupled to efficient cell migration is a hallmark of high metastatic potential.
Current state-of-the-art practice for prognostication and treatment is limited, especially for invasive tumors. Although the expression of several genes and proteins associated with PI3K-Akt signaling, actin remodeling, motility and invasion has been shown to vary among tumors, only a few of these markers are suitable for prognostication purposes. Thus, there is a persistent need for new biomarkers that play a critical role during tumor invasion, that are mechanistically well characterized, and that may also serve to stratify the clinical risk of metastasis among cancer patients.
Existing therapies in cancer invasion center around the pharmacologic blockade of individual receptor pathways such as VEGFR and EGFR pathways. However, in most carcinomas, including colon, breast and lung carcinomas, rapid resistance develops to single or combination receptor blocking therapies. Moreover, relapsed tumors are often more aggressive under these circumstances. Thus, new molecular targets are needed that are involved in the regulation of multiple signaling pathways, the inhibition of which may result in more efficacious treatments than single receptor blocking therapies. Additionally, many traditional kinase inhibitors targeting the kinase-domain suffer from severe dose-limiting toxicity. Alternative targets are therefore desired to create further options for the regulation of kinase activities, for example by interfering with the interaction between the kinase and another protein cofactor.